tbuckley/cabot-search huggingface dataset:
Simultaneous expression of androgen receptor and tumor-associated neutrophil in breast cancer subtypes.
Authors: Minoosh Moghimi, Shahin Vadoudi, Majid Amirian, Farzane Ahmadi, Mohammad Borna Amirian, Kasra Khodadadi, Reza Mansouri
Journal: Journal of Clinical Oncology (2023)

e12539 Background: Considering the heterogeneity of breast cancer phenotypes and different response rates to treatment, it is essential to determine prognostic markers that could confer therapeutic role as well. In this study, androgen receptor (AR) and tumor-associated neutrophil (TAN) in female breast cancer were investigated and their coherency with different subtypes of breastcancer and pathology findings were assessed. Methods: This cross-sectional study was conducted on patients with Stage I-IV breast cancer who were referred to Borna Pathology Center in Zanjan, Iran during 2018-2021. The tumoral paraffine blocks were evaluated for AR (by the IHC method) and TAN (by morphology and the IHC staining for myeloperoxidase). Relationships in different subtypes and stages were assessed.Using univariate logistic regression between 5 subtypes (defended by ER, PR, HER2, and Ki67), stage, age, metastasis (M), and grade with AR and TAN were studied separately and simultaneously. Results: We collected data from 83 women with Stage I-IV breast cancer with mean ± SD age of diagnosis 49.3±11.2 years. Percentage of AR+, TAN+, and AR+&amp;TAN+ were 71.1, 43.4, and26.5, respectively. The frequency of AR+ and AR-&amp;TAN- was high in hormone-positive subtypes, while TAN+ was frequent in the triple-negative group and AR+&amp;TAN+ in Luminal A and B groups. The relation between age, M, and Stage with AR, TAN, and AR &amp; TAN was not significant. AR was significantly related to subtype and grade. Conclusions: AR+ probability was significantly lower in Triple Negative subtype and poorly differentiated grade. Based on the heterogeneity of the presentation of these markers, survival evaluation can be important in risk assessment of them. Relationship between AR, TAN, and AR&amp;TAN with study variables. [Table: see text]
Fertility preservation in women with cancer in Brazil: Infertility specialists' perceptions and attitudes.
Authors: Warne Pedro Andrade, Rivia Mara Lamaita, Renata Lack Rannige, Angelica Nogueira Rodrigues, Agnaldo Lopes silva-Filho
Journal: Journal of Clinical Oncology (2023)

e13676 Background: Oncofertility is a universal right and a global oncology priority. However, there is a lack of communication between infertility specialists and their clinical oncologists on topics relating to fertility preservation. The present study aims to evaluate the perceptions and attitudes of infertility specialists regarding fertility preservation in women with cancer in Brazil. Methods: An online questionnaire was sent to infertility specialists affiliated to the Brazilian Federation of Associations of Gynecology and Obstetrics (FEBRASGO, in the Portuguese acronym). Results: A total of 100 (30.9%) of 323 FEBRASGO infertility specialists responded, most located in the southern and southeastern Brazilian states. Experience in Human Reproduction ranged from one to 40 years (mean ± standard deviation: 15.5 ±10.2 years). Considering women with cancer in reproductive age in whom fertility preservation was indicated, 60.3% ±28.8% of them performed the procedure (ranging from 10 to 100%). Three main barriers to fertility preservation were appointed: cost (41%), knowledge and acceptance of medical oncologists (35%) and accessibility (9%). Most infertility specialists (58%) considered age above 40 years as the limit for fertility preservation in women with cancer. Breast and ovarian cancers, leukemia, and lymphoma were considered the most relevant types to be considered for fertility preservation, while lung, thyroid, gastric and brain. Conclusions: This is the first Brazilian study on specialists' impressions on cancer patient's access to fertility preservation. While most Brazilian cancer patients are treated in the public health system, most fertility specialists are in the private sector. Currently, the model of care is fragmented and a more integrated workflow between cancer and fertility experts is fundamental to improve fertility sparing access. Further studies are needed on the topic, also including clinical oncologists, hematologists, breast cancer specialists, and patients.
Circulating tumor DNA (ctDNA) monitoring in patients with breast cancer receiving neoadjuvant palbociclib and endocrine therapy: A secondary analysis of the NeoRHEA phase 2 study.
Authors: Alexandra Stanciu, Andreas Papagiannis, Christodoulos Pipinikas, Nathan Campbell, Mariana Brandão, Frederic Cailleux, Elisa Agostinetto, Lieveke Ameye, Marianne Paesmans, Tatiana Besse-Hammer, Ahmad Awada, Martine J. Piccart-Gebhart, Christos Sotiriou, Patrick Neven, Francois P. Duhoux, Nitzan Rosenfeld, Peter Vuylsteke, Michail Ignatiadis
Journal: Journal of Clinical Oncology (2023)

601 Background: Personalized circulating tumor DNA (ctDNA) assays are being evaluated in early breast cancer (BC). We investigated the value of ctDNA monitoring in the NeoRHEA study. Methods: NeoRhea (NCT03065621) is a single arm phase 2 study in which patients with estrogen receptor (ER)+/HER2- early breast cancer were treated with neoadjuvant palbociclib + endocrine therapy (ET) for 4 months. Plasma samples were collected at four timepoints: pre-treatment (BL), after the first treatment cycle (C1D28), before surgery (Surgery) and one month post Surgery (End of Study). ctDNA detection was evaluated using the personalized RaDaR assay. Whole-exome sequencing (WES) was performed on BL tumor biopsies followed by a personalized assay development using tumor, plasma and normal DNA in order to track up to 48-patient specific somatic variants in plasma cell-free DNA (cfDNA) using next generation sequencing. Associations between ctDNA detection and BL clinical-pathological characteristics, cell cycle arrest (CCCA) defined as Ki67 ≤2.7% at surgery, residual cancer burden (RCB) rate and breast cancer free survival (BCFS) were investigated. Results: Of 100 patients enrolled, 78 patients and 302 plasma samples were successfully profiled by the RaDaR assay. The number of variants targeted by the assay ranged between 7-48 (median = 25). The median estimated variant allele fraction for ctDNA positive samples was 0.02% (range 0.0009%-0.91%). A total of 42/76 patients were ctDNA positive at BL, 4/76 at C1D28, 4/75 at Surgery and 0/75 at End of Study. Out of 78 patients, 68% were postmenopausal, 78 % had cT2 and 69% cN0 tumors, 20% had multifocal/multicentric tumors, 18% had histological grade 3 tumors, 76% had CCCA (Ki67 not available in 20 patients) and 34% RCB 3 at surgery. ctDNA detection at BL was higher in histological grade 3 tumors (p = 0.03), lower in multifocal/multicentric tumors (p = 0.01), higher in RCB III tumors, (p = 0.01) but was not associated with CCCA. With a median follow-up of 3.8 years (range 1-5 years), 4 patients developed distant and one patient locoregional recurrences. ctDNA detection after one month of treatment (logrank p = 0.02), but not at baseline (p = 0.59) nor at surgery (p = 0.67) was associated with worse BCFS. Conclusions: Detection of ctDNA in early-stage breast cancer is challenging. Our data suggests association of ctDNA detection with some pathological and clinical variables. Independent validation is needed. Clinical trial information: NCT03065621 .
Outcomes with first-line (1L) ribociclib (RIB) + endocrine therapy (ET) vs physician’s choice combination chemotherapy (combo CT) by age in pre/perimenopausal patients (pts) with aggressive HR+/HER2− advanced breast cancer (ABC): A subgroup analysis of the RIGHT Choice trial.
Authors: Nagi S. El Saghir, Yoon Sim Yap, Yesim Eralp, Seock-Ah Im, Hamdy A. Azim, Julie Rihani, Nikita Volkov, Shin-Cheh Chen, Hakan Harputluoglu, Patrapim Sunpaweravong, Yuan-Ching Chang, Teresa Delgar Alfaro, Jiwen Wu, Huilin Hu, Ming Gao, Yen-Shen Lu
Journal: Journal of Clinical Oncology (2023)

1063 Background: The progression-free survival (PFS; primary endpoint) results from the Phase II RIGHT Choice trial demonstrated a statistically significant median PFS (mPFS) benefit of ≈1 y with RIB + ET over combo CT (mPFS, 24.0 vs 12.3 mo; hazard ratio [HR], 0.54; 95% CI, 0.36-0.79; P = .0007) in pts with aggressive HR+/HER2− ABC. Younger pts with aggressive ABC have a worse prognosis, which impacts treatment (tx) decisions. Hence, a subgroup analysis of key efficacy endpoints from RIGHT Choice by age (&lt; 40 vs ≥ 40 y) was undertaken. Methods: Pre/perimenopausal pts (aged 18-59 y) with HR+/HER2− ABC and no prior systemic therapy for ABC were randomized 1:1 to either RIB with letrozole/anastrozole + goserelin or investigator’s choice of combo CT (docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine). Pts in the trial had ABC not amenable to curative therapy and for which combo CT was clinically indicated by physician’s judgment (ie, symptomatic visceral metastases, rapid progression of disease or impending visceral compromise, or markedly symptomatic non-visceral disease). Results: In total, 70 pts were aged &lt; 40 y and 152 were aged ≥ 40 y. In the combo CT arm, pts aged &lt; 40 y fared worse and had a shorter mPFS, shorter median time to tx failure (mTTF), and higher 3-month tx failure rate (TFR) than pts aged ≥ 40 y. Pts aged &lt; 40 y showed a significant PFS benefit with RIB + ET vs combo CT (mPFS, not reached [NR] vs 10.2 mo; HR, 0.38). This PFS benefit with RIB + ET over combo CT was also observed in pts aged ≥ 40 y (21.2 vs 16.0 mo; HR, 0.71). Regardless of age, the mTTF was longer and the 3-month TFR was lower in the RIB + ET arm than the combo CT arm. The median time to response (mTTR), overall response rate (ORR), and clinical benefit rate (CBR) were similar between the two tx arms in both age groups. Conclusions: This analysis demonstrated a clinically meaningful PFS benefit and improved secondary outcomes with 1L RIB + ET over combo CT along with similar treatment responses in both tx arms in pts aged &lt; 40 y as well as in those ≥ 40 y with aggressive HR+/HER2− ABC. This analysis supports RIB + ET as a preferred tx option in this pt population, including younger pts aged &lt; 40 y. Clinical trial information: NCT03839823 . [Table: see text]
Prediction of cancer treatment response from histopathology images through imputed transcriptomics.
Authors: Danh-Tai Hoang, Gal Dinstag, Leandro C. Hermida, Doreen Ben-Zvi, Chani Stossel, Tejas Patil, Stephen-John Sammut, Wiem Lassoued, Clint Allen, Tuvik Beker, Peng Jiang, Talia Golan, Adam G. Sowalsky, Sharon R Pine, Carlos Caldas, James L. Gulley, Kenneth D. Aldape, Ranit Aharonov, Eric Stone, Eytan Ruppin
Journal: Journal of Clinical Oncology (2023)

1551 Background: In recent years, the use of tumour molecular profiling within the clinic has allowed for more accurate cancer diagnostics, as well as the delivery of precision oncology. Rapid advances in digital histopathology have allowed the extraction of clinically relevant information embedded in tumor slides by applying machine learning methods, capitalizing on recent advancements in image analysis via deep learning. However, as in many supervised learning approaches, predicting response to therapy using whole slide images (WSI) of tissue stained with hematoxylin and eosin (H&amp;E) requires large datasets comprising matched imaging and response data, severely restricting the applicability of this approach. Methods: To overcome this critical challenge, we introduce here for the first time a generic methodology for generating WSI-based predictors of patients’ response for a broad range of cancer types and therapies, which does not require matched WSI and response data for training. The approach, termed ENLIGHT-DeepPT, consists of: (1) DeepPT, a new deep-learning framework that predicts exome-wide tumor mRNA expression from slides, and (2) ENLIGHT, a recently published response prediction algorithm, applied here to predict response based on the DeepPT predicted expression values, instead of measured values. Results: First, we study the ability to predict tumor expression, showing that DeepPT successfully predicts transcriptomics in all 16 TCGA cohorts tested and generalizes well to two independent datasets. Second, aligned with our key aim, we analyze six independent clinical trial datasets of patients with different cancer types that were treated with various targeted and immune therapies, on which DeepPT was never trained. We show that ENLIGHT, without any adaptation, can successfully predict the true responders from the expression values imputed by DeepPT, using only H&amp;E images: ENLIGHT-DeepPT successfully predicts true responders in these cohorts with an overall odds ratio of 2.19, increasing the baseline response rate by 38.8% on average among predicted responders. Conclusions: ENLIGHT-DeepPT is the first approach to successfully predict response to multiple targeted and immune cancer therapies directly from H&amp;E slides, without requiring any drug-specific training data. ENLIGHT-DeepPT can provide rapid treatment recommendations without requiring tumor sequencing, bringing precision oncology to low-income countries and other situations where NGS is prohibitive.
Impact of geography on receipt of medical oncology consultation and neoadjuvant chemotherapy for triple negative and HER2 positive breast cancer.
Authors: Elliott Kenneth Yee, Julie Hallet, Nicole Jannelle Look Hong, Lena Nguyen, Natalie G. Coburn, Frances Catriona Wright, Sonal Gandhi, Katarzyna Joanna Jerzak, Andrea Eisen, Amanda Roberts
Journal: Journal of Clinical Oncology (2023)

1530 Background: Consensus guidelines recommend consideration of neoadjuvant chemotherapy (NAC) for most patients with early-stage triple negative (TN) and HER2 positive (HER2+) breast cancer. Based on our previous work, most patients are not seen by a medical oncologist prior to surgery and do not receive NAC. Although potential barriers are not well understood, distance to cancer centres has been shown to mediate medical oncology referral and use of systemic therapy for other malignancies. We therefore aimed to characterize the impact of region of residence and cancer centre proximity on receipt of pre-treatment medical oncology consultation and NAC for patients with TN and HER2+ breast cancer. Methods: Using linked administrative healthcare datasets in Ontario, Canada, we performed a retrospective population-based geographic analysis of women diagnosed with stage I-III TN or HER2+ breast cancer from 2012-2019. Outcomes were pre-treatment medical oncology consultation and initiation of NAC. We created choropleth maps to assess the spatial distribution of outcomes across census divisions, displaying cancer centres and outcomes by colour gradient using geographic information system analysis. To assess the relationship between distance to the nearest cancer centre and outcomes, we performed a multivariable regression analysis adjusted for sociodemographic and clinical factors, including tumour extent and nodal status. Results: Within the cohort of 12,881 patients, there was no statistically significant relationship between incremental distance to the nearest cancer centre (≤5 vs. 5-10, 10-25, and ≥25 km) and rate of medical oncology consultation or receipt of NAC. Mapping analysis demonstrated high interregional outcome variability, ranging across census divisions from 12.2% to 64.3% for medical oncology consultation rate, and 9.3% to 64.3% for NAC rate. 77.7% of patients referred to medical oncology received NAC. Conclusions: Among patients with TN and HER2+ early breast cancer, rates of medical oncology consultation and NAC were not significantly impacted by distance to cancer centres but varied highly by region. This variability suggests that regional and/or provider practice patterns, rather than distance, may underlie discrepancies in referral for NAC. These findings can inform further studies and interventions aiming to improve equitable access to NAC for patients with TN and HER2+ breast cancer.
A novel pan-RAS inhibitor for luminal B breast cancer.
Authors: Tariq Arshad, Howard Donninger, Joe Burlison, Mike Sabo, John Trent, Geoffrey J. Clark
Journal: Journal of Clinical Oncology (2023)

e13132 Background: Luminal B breast cancer makes up between 10-20% of cases and is among the most lethal forms of breast cancer. Prognosis is little better than that of the notorious Triple Negative disease. There is currently no effective treatment for Luminal B breast cancer. Recently it has been found that, although mutations in the RAS oncogene are rare in Luminal B, hyper activation of the wild type RAS protein is common due to inactivation of key negative regulators of RAS such as DAB2IP and RASAL. Therefore, targeting RAS is a logical novel approach to developing enhanced therapy for this disease. There are three main isoforms of RAS and there are no currently approved pan-RAS inhibitors. We have developed a small molecule pan-RAS inhibitor which binds directly to all forms of RAS. It acts to block the ability of RAS and to bind and signal through its effectors by disrupting the RAS effector domain. It is active in vitro and in vivo against models of Luminal B breast cancer. Methods: In silico screening of a virtual compound library was performed to identify an initial candidate inhibitor. Iterative rounds of Medicinal Chemistry informed by structural modeling and bioassay in 3D vs 2D growth assays were performed to identify an enhanced activity derivative. Target binding was confirmed by Microscale Thermophoresis and NMR. RAS/RAF complex status was measured by co-immunoprecipitation of the endogenous proteins. Ras signaling was assayed by Western analysis of Phospho-ERK and RAL-GTP pull down assays. In vitro activity was measured using 3D soft agar assays. In vivo activity was measured by ip or po administration against a Luminal B breast cancer cell line. Results: The current lead, designated RAS-F binds all three main isoforms of RAS at low uM kd and modulates the RAS effector domain in NMR studies. It suppresses RAS signaling pathways in transient assays and suppresses Luminal B tumor cell tumor cell growth in soft agar and in vivo. Conclusions: We have developed a pre-clinical pan-RAS inhibitor that is active in vitro and in vivo against Luminal B breast cancer models. The agent also has potential uses against other tumor types partially driven by deregulated wild type RAS such as triple negative breast cancer.
Prospective phase I study of checkpoint blockade for the treatment of patients with newly diagnosed high-grade glioma prior to radiochemotherapy: Results of nivolumab plus ipilimumab treatment arm.
Authors: Santosh Kesari, Alexandre Wojcinski, Jaya M. Gill, Jose Arganda Carrillo, Naveed Wagle, Minhdan Nguyen, Judy Dang Truong, Tiffany M. Juarez
Journal: Journal of Clinical Oncology (2023)

2057 Background: The limited success of checkpoint inhibitors (CPI) targeting the programmed death-1 (PD-1) axis in the adjuvant setting for glioblastoma has prompted a deeper understanding of the brain tumor and immune microenvironment and evaluating how the sequence of immunotherapy administration impacts antitumor response. We initiated a feasibility study (NCT03425292) of postoperative nivolumab (anti-PD-1) monotherapy and combination therapy in adults with newly diagnosed high-grade gliomas (HGG) prior to radiotherapy. Methods: Within six weeks from surgical resection of newly diagnosed HGG, patients in study Arm 3 received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. The primary endpoint was the rate of dose-limiting toxicities (DLT). Secondary objectives included adverse events, antitumor activity and pharmacodynamic effects of study treatment. Next-generation sequencing (NGS) was performed on archival tumor specimens before treatment and at the time of subsequent surgery. Results: Fifteen patients were treated with nivolumab plus ipilimumab. 27% (4/15) of patients were receiving dexamethasone at treatment initiation. MGMT promoter was methylated in 5 tumors, unmethylated in 9, and equivocal in one. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased (n = 2), anorexia (n = 1), pruritus (n = 1), and rash (n = 3), and Grade 4 cerebral edema occurred in 1 patient. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months. Paired tumor specimens obtained before and after treatment were analyzed in six patients and revealed molecular changes in response to treatment as well as differences between patients with shrinking tumors versus progressing tumors. Conclusions: We show that nivolumab plus ipilimumab can be safely administered prior to radiation. To our knowledge, this is the first study in which checkpoint blockade therapy was administered for newly diagnosed glioblastoma prior to standard radiotherapy. Despite the short mPFS, mOS was suggestive of a potential long-term benefit from early CPI exposure, and three patients deferred chemoradiation greater than seven months. Analysis of other study arms is ongoing. Clinical trial information: NCT03425292 .